Evidence from genetic, biochemical, and neuropathological studies has shown that loss of homeostatic microglia function contributes to Alzheimer?s disease (AD) pathogenesis. From our work and the work of others, dystrophic microglia are now known to be a common feature of AD and other neurodegenerative diseases, but little is known about the causes and consequences of dystrophic microglia in AD. Our pilot data from an unbiased proteomic screening of AD brains has identified ferritin light chain (FTL) as a top candidate protein. FTL is used to store excess iron in microglia. Prior studies have shown that dystrophic microglia in the AD brain express high amounts of ferritin. Regulation of iron homeostasis occurs by the influx, storage, and efflux of iron from cells. Our project is a departure from prior work on microglia in AD, as we will define the mechanisms leading to a primary glial pathology ? dystrophic microglia. Our hypothesis that dysregulation of iron homeostasis is a driving force in microglial degeneration is novel. By using complementary histological, biochemical, and flow cytometry methods in human brain tissue, we will define this human-specific glia degeneration. We hypothesize that a dysregulation of iron homeostasis is a driver of dystrophic microglia in neurodegenerative disease. Using biosamples from the University of Kentucky Alzheimer?s Disease Center biobank of well-characterized tissue encompassing the full spectrum of disease severity, we will address the following specific aims: Aim 1: Define iron influx pathway in dystrophic microglia Aim 2: Define iron storage pathway in dystrophic microglia Aim 3: Define iron efflux pathway in dystrophic microglia Overall impact: Successful completion of this project will lead to the discovery of a novel target, in microglia iron homeostasis, to restore the healthy function of microglia, and prevent the degeneration of these cells.